The present invention relates generally to screening tests to determine which patients are at risk for developing angioedema associated with inhibitors of angiotensin converting enzyme (ACE) and/or combined ACE and neutral endopeptidase (NEP) inhibitors (a combined ACE/NEP inhibitor is referred to herein as a xe2x80x9cvasopeptidase inhibitorxe2x80x9d). More particularly, the present invention relates to an association between dipeptidyl peptidase IV (DPP IV) and aminopeptidase P (APP) enzymatic activity and ACE and vasopeptidase inhibitor-related angioedema. The present invention also provides screening tests and kits to identify a subject who is at risk for ACE and vasopeptidase inhibitor-associated angioedema.
Administration of angiotensin-converting enzyme (ACE) inhibitors is common medical practice for the treatment of a variety of disease conditions, including: cardiac and renal diseases, diabetes, and hypertension (high blood pressure). Several combined ACE and neutral endopeptidase (NEP) inhibitors are presently under investigation or are awaiting regulatory approval for the treatment of the aforementioned disease conditions. However, the administration of an ACE and/or a vasopeptidase inhibitor (referred to herein as an ACE/vasopeptidase inhibitor) is contraindicated for subjects with a history of angioedema due to the potential severity of this side effect, which can be so severe as to result in death. Approximately 0.1% to 1.0% of the population receiving an ACE inhibitor is predicted to be susceptible to developing at least one episode of angioedema during treatment. This percentage might be even higher, especially for subjects taking a vasopeptidase inhibitor. Also, these inhibitors are often administered over long periods of time because the illnesses that they treat are often chronic conditions. This could increase the chances of a subject developing angioedema over a course of treatment.
Angioedema is an uncommon, but serious, side effect of ACE and vasopeptidase inhibitors. Currently, it is not possible to accurately predict which subjects are at risk to develop angioedema when taking an ACE or vasopeptidase inhibitor; however it is known that approximately 0.1% to 1.0% or more of the subjects receiving an ACE or vasopeptidase inhibitor will develop angioedema as a side effect. The variation in susceptibility to vasopeptidase-associated angioedema depends, in part, on the subgroup of the population that is analyzed. For example, African Americans are particularly susceptible to ACE inhibitor associated angioedema.
In patients who develop angioedema while taking one of these medications, it is difficult to determine if the angioedemic condition arose in response to the medication or due to some other occurrence. For example, certain allergic reactions can result in angioedema. The current standard in practice is to employ a treatment other than an ACE/vasopeptidase inhibitor, if a patient has a known history of angioedema, or to halt treatment with ACE/vasopeptidase inhibitors if a patient presents with symptoms of angioedema or it is learned after-the-fact that the patient has a history of angioedema. Most practitioners, however, consider these alternative therapies to be less effective in treating the original condition than ACE/vasopeptidase inhibitor therapy.
What is needed, therefore, are tests, assays, and biological markers for identifying patients that are at increased risk for developing angioedema related to treatment with ACE/vasopeptidase inhibitors, as compared to the general population or a matched population. Such assays would allow the continued use of ACE/vasopeptidase inhibitors in subjects that have a reduced susceptibility to angioedema and the rational regulation of their use in susceptible subjects. The present invention solves these and other problems, in part by providing biological markers and diagnostic tests and kits that are preferably employed early on in treatment, thereby averting complications.
A method of identifying a subject that is susceptible to developing an angioedemic condition during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the method comprises (a) providing a biological sample obtained from a subject; (b) determining a dipeptidyl peptidase IV activity in the biological sample; and (c) comparing a dipeptidyl peptidase IV activity in the biological sample to a standard dipeptidyl peptidase IV activity, wherein a 10% or more reduction in the sample activity compared to the standard indicates that the subject is susceptible to developing an angioedema during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor. Preferably, the vasopeptidase inhibitor is an angiotensin-converting enzyme inhibitor or a neutral endopeptidase inhibitor. It is also preferable that a 20% or more reduction in the sample activity compared to the standard indicates that the subject is susceptible and that the subject is a human.
A method of identifying a subject that is susceptible to developing an angioedemic condition during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the method comprises: (a) providing a biological sample obtained from a subject; (b) determining an aminopeptidase P activity in the biological sample; and (c) comparing an aminopeptidase P activity activity in the biological sample to a standard aminopeptidase P activity, wherein a 10% or more reduction in the sample activity compared to the standard indicates that the subject is susceptible to developing an angioedema during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor. Preferably, the vasopeptidase inhibitor is an angiotensin-converting enzyme inhibitor or a neutral endopeptidase inhibitor. It is also preferable that a 20% or more reduction in the sample activity compared to the standard indicates that the subject is susceptible and that the subject is a human.
A method of determining contraindication for administration of one of an ACE inhibitor and a vasopeptidase inhibitor to an individual is disclosed. In a preferred embodiment, the method comprises: (a) providing a biological sample obtained from a subject; (b) determining a dipeptidyl peptidase IV activity in the biological sample; and (c) comparing a dipeptidyl peptidase IV activity in the biological sample to a standard dipeptidyl peptidase IV activity, wherein administration of the vasopeptidase inhibitor is contraindicated when the dipeptidyl peptidase IV activity in the biological sample is outside the standard dipeptidyl peptidase IV activity range.
A method of determining contraindication for administration of one of an ACE inhibitor and a vasopeptidase inhibitor to an individual is disclosed. In a preferred embodiment, the method comprises: (a) providing a biological sample obtained from a subject; (b) determining an aminopeptidase P activity in the biological sample; and (c) comparing an aminopeptidase P activity in the biological sample to a standard aminopeptidase P activity, wherein administration of the vasopeptidase inhibitor is contraindicated when the aminopeptidase P activity in the biological sample is outside the standard aminopeptidase P activity range.
A method of screening an individual for compatibility with an administration of one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the method comprises: (a) providing a biological sample obtained from a subject; (b) determining a dipeptidyl peptidase IV activity in the biological sample; and (c) comparing a dipeptidyl peptidase IV activity in the biological sample to a standard dipeptidyl peptidase IV activity range, wherein administration of the vasopeptidase inhibitor is contraindicated when the sample activity is outside the standard dipeptidyl peptidase IV activity range, and wherein administration of the vasopeptidase inhibitor is indicated when the sample activity is either within or above the standard dipeptidyl peptidase IV activity range. Preferably, the vasopeptidase inhibitor is an angiotensin-converting enzyme inhibitor or a neutral endopeptidase inhibitor.
A method of screening an individual for compatibility with an administration of one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the method comprises (a) providing a biological sample obtained from a subject; (b) determining an aminopeptidase P activity in the biological sample; and (c) comparing an aminopeptidase P activity in the biological sample to a standard aminopeptidase P activity range, wherein administration of a vasopeptidase inhibitor is contraindicated when the sample activity is below the standard aminopeptidase P activity range, and wherein administration of the vasopeptidase inhibitor is indicated when the sample activity is either equal to or above the standard aminopeptidase P activity range. Preferably, the vasopeptidase inhibitor is an angiotensin-converting enzyme inhibitor or a neutral endopeptidase inhibitor.
A kit for identifying a subject at risk for angioedema during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the kit comprises: (a) a substrate of a dipeptidyl peptidase IV enzyme; (b) a buffer; (c) a reaction stop solution; and (d) a set of instructions comprising information on a standard dipeptidyl peptidase IV activity range. Preferably, the article of manufacture further comprises a calibration solution for calibration of the reaction and the substrate is Gly-Pro-p-nitroanilide.
A kit for identifying a subject at risk for angioedema during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the kit comprises: (a) an aminopeptidase P enzyme substrate; (b) a dilution buffer; (c) a reaction stop solution; (d) a revelation buffer; and (e) a set of instructions comprising information on a standard aminopeptidase P activity range. Preferably, the article of manufacture further comprises a calibration solution for calibration of the reaction and the substrate is the peptide Arg-Pro-Pro.
A kit for identifying a subject at risk for angioedema during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the kit comprises (a) a vasopeptidase inhibitor; and (b) a packaging material comprising information that the vasopeptidase inhibitor is contraindicated for individuals with a serum dipeptidyl peptidase IV enzyme activity outside a standard dipeptidyl peptidase IV activity range.
A kit for identifying a subject at risk for angioedema during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor is disclosed. In a preferred embodiment, the kit comprises (a) a vasopeptidase inhibitor; and (b) a packaging material comprising information that the vasopeptidase inhibitor is contraindicated for individuals with a serum aminopeptidase P enzyme activity outside a standard aminopeptidase P activity range.
Another kit is disclosed and in a preferred embodiment comprises a vasopeptidase inhibitor and a packaging material, wherein the packaging material includes information that the vasopeptidase inhibitor is contraindicated for individuals with a dipeptidyl peptidase IV enzyme activity below a normal range or is indicated for individuals with a dipeptidyl peptidase IV enzyme activity within a normal range.
Another kit is disclosed and in a preferred embodiment comprises a vasopeptidase inhibitor and a packaging material, wherein the packaging material includes information that the vasopeptidase inhibitor is contraindicated for individuals with an aminopeptidase P enzyme activity below a normal range or is indicated for individuals with an aminopeptidase P enzyme activity within a normal range.
A method of marketing a vasopeptidase inhibitor is disclosed and in a preferred embodiment, the method comprises providing information about a diagnostic test adapted to identify a subject that is susceptible to angioedema as a result of taking the vasopeptidase inhibitor during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor. Preferably, the vasopeptidase inhibitor is an angiotensin-converting enzyme inhibitor, the diagnostic test comprises detecting an activity of a dipeptidyl peptidase IV enzyme or an aminopeptidase P enzyme in a biological sample from the subject, and the subject is a human. It is also preferable that the vasopeptidase inhibitor is a neutral endopeptidase inhibitor that the diagnostic test includes detecting an activity of a dipeptidyl peptidase IV enzyme or an aminopeptidase P enzyme in a biological sample from the subject, and the subject is a human.
Accordingly, it is an object of the present invention to provide a novel method and article for identifying a subject that is susceptible to developing an angioedemic condition during a course of treatment comprising administering one of an ACE inhibitor and a vasopeptidase inhibitor. This and other objects are achieved in whole or in part by the present invention.
An object of the invention having been stated hereinabove, other objects will be evident as the description proceeds, when taken in connection with the accompanying Drawings and Laboratory Examples as best described hereinbelow.